Natural whole blood is oftentimes in short supply. New methods for prolonged preservation of blood in the frozen state and improvements in storage in the liquid state have resulted in more efficient use of available blood in some areas, but the world-wide need for blood for transfusion still exceeds the supply. Since it is unlikely that there will be any appreciable increase in supply, the need for blood for transfusion must be satisfied in some manner other than natural blood or its derivatives. An artificial blood, available in unlimited quantities and free from infectious agents and antigens, would be an extremely valuable therapeutic agent.
A number of years ago, the oxygen-carrying capacity and lack of toxicity of perfluorinated liquids were reported. Emulsions of fluorocarbon liquids were used as artificial bloods. In brief, over nearly the last 20 years, considerable work has been accomplished in connection with the use of fluorocarbons and fluorocarbon emulsions as oxygen transfer agents and as artificial bloods. It is inevitable that artificial blood will be commercialized and used throughout the world because of the significant need for such oxygen transport agents and the advantages of such agents over natural blood.
The most prominent requirements of an artificial blood substitute are efficient oxygen and carbon dioxide transport, biological inertness, lower vapor pressure and dispersibility to form emulsions.
Several synthetic fluorocarbon compounds are known to be useful as blood substitutes. Such compounds are described in U.S. Pat. No. 3,911,138 (Clark, 1975), which describes emulsions that contain perfluorinated cyclic hydrocarbons, and U.S. Pat. Nos. 4,110,474 and U.S Pat. No. 4,187,252 (Lagow et al, 1978 and 1980), which describe emulsions that contain perfluorotetramethylpentane. U.S. Pat. No. 3,911,138 sets forth the various advantages and needs for artificial blood and may be referred to as further background of this invention. Continuing work is being done to create and identify other compounds which are suitable as blood substitutes, perfusion media, breathable liquids, and for other biological and chemical purposes. Such compounds are likely to have superior qualities regarding one or more relevant characteristics, which include: oxygen affinity and release, solubility or emulsifiability in various media, low toxicity, high shelf life, appropriate stability within the body, low retention within vital organs of the body, and low cost of manufacture.
Emulsions made from perfluorocyclo compounds have been found useful as blood substitutes because the cyclic fluorocarbon is transpired by the body through the skin and the lungs. However, in order for these emulsions to be preferred for biological use, they must be freshly prepared because they are not stable. In the emulsion, the particles making up the internal phase (dispersed phase) consist of globules of fluoro compounds which are immiscible with the aqueous external phase (dispersion medium). The stability of the internal phase in the fluorochemical emulsion is important since the greater the stability, the longer the emulsion can be safely stored before it is used in vivo. In addition, if the emulsion is very stable, it can be stored without refrigeration; this characteristic is critical for military purposes and in countries where there is little or no refrigeration. Furthermore, a stable emulsion is more predictable from a medical standpoint compared to an emulsion which tends to deteriorate with time. Normally, after administration to an animal, and thus exposure to body temperatures, the internal phase of the emulsion may convert to larger globules. Much remains to be learned about the factors working for and against the emulsion stability in the blood stream and tissues of mammals. While it seems reasonable to suppose that factors which would make for an in vitro stability also make for in vivo stability, there are also special considerations involved in promoting in vivo stability of foreign particles such as perfluorochemical particles. All of the above points to the need for improvements in oxygen transport agents for artificial bloods.
The need for suitable oxygen transport agents is particularly acute at the present time due to the widespread reporting and publicity on acquired immune deficiency syndrome (AIDS). The acquired immune deficiency syndrome virus is also known as HTLV-III. There is no known cure for acquired immune deficiency syndrome which destroys the body's ability to fight cancer and even minor infections. The implication of natural human blood transfusions as an important vector in the propagation of acquired immune deficiency syndrome has magnified the need for an alternative blood replacement fluid. The fact that an HTLV-III blood test has been developed to screen blood donated to blood banks has not decreased the need for the discovery of suitable oxygen transport agents.
Triethylenediamine (1,4-diazabicyclo-[2,2,2]-octane) is a compound which was first reported by Otto Hromatka "Uber das Triethylendiamin (Bicyclo-[2.2.2]-diaza-1.4-octan)" in Berichte der Deutchen Chemischen Gesellschaft, 75:1303-1310 (1942) and Otto Hromatka and Eva Engel "Uber das Triethylendiamin (Bicyclo [2.2.2]-1.4-diaza-octan), II. Mitteilung" in Berichte der Deutchen Chemischen Gesellschaft, 76:712-722 (1943) as a reaction product of diethanolamine hydrochloride and sodium hydroxide.
As indicated in the Journal of Chemical and Engineering Data, Vol. 4, no. 4 (1959) pp. 334-335, triethylenediamine exhibits certain unusual properties which are due to its bicyclic or "cage" structure. The most outstanding properties, such as high melting point and complexing ability, arise from the molecular symmetry and the lack of steric hinderance for both tertiary nitrogen atoms. Triethylenediamine has found a special commercial application as a catalyst in polyurethane foam manufacture. In this application, triethylenediamine's ability to catalyze reactions between isocyanates and hydroxy compounds with great rapidity and yet with a desired balance between rate of foaming and chain growth, is outstanding. Houdry Process Corporation, Linwood, Pa., commercialized triethylenediamine under the name of DABCO.RTM. as a catalyst for the preparation of urethanes following U.S. Pat. No. 2,939,851. It determined that the combination of low basicity with a high vaporization and condensation coefficient which are common to symmetrical cage compounds, promote quick curing of urethane foams which is essential to fast mold release. This cage structure may be beneficial in other applications.
In U.S. Pat. No. 3,335,143, Erner described the fluorination of triethylenediamine by electrolysis of a hydrogen fluoride solution of triethylenediamine in perfluorohexane using a nickel Simon's cell to obtain perfluorotriethylenediamine. ##STR1##
As used herein, perfluorotriethylenediamine indicates that all of the replaceable hydrogen atoms in triethylenediamine have been replaced by fluorine atoms. Perfluorotriethylenediamine is a solid with a melting point above 120.degree. C., which, like its parent triethylenediamine, sublimes rapidly upon heating. Perfluorinated triethylenediamine can also be prepared from triethylenediamine by direct fluorination using elemental fluorine as a minor constituent of an inert gas such as argon.